Miller Fisher Syndrome (MFS) in the Context of COVID-19: A Comprehensive Review


Miller Fisher Syndrome (MFS) is a rare neurological disorder that falls under the umbrella of Guillain-Barré syndrome (GBS) variants.

It was initially described by Collier in 1932 but gained its eponym from the contributions of Miller Fisher in 1956, who reported three cases exhibiting the characteristic triad of ataxia, ophthalmoplegia, and areflexia. MFS represents a minute subset of GBS cases, accounting for approximately 5% of all GBS patients.

Epidemiology and Diagnostic Markers

The worldwide incidence of GBS is estimated to be one to two cases per 100,000 individuals, with MFS constituting an even smaller proportion, approximately one to two cases per 1,000,000. A distinctive feature in MFS diagnosis is the presence of normal white blood cell (WBC) counts in cerebrospinal fluid (CSF) but elevated protein levels, a phenomenon termed albuminocytological dissociation (ACD).

Another diagnostic marker for MFS is the presence of anti-GQ1b IgG antibodies, specifically targeting ganglioside GQ1b. Additionally, electroneuromyography (EMG) and magnetic resonance imaging (MRI) may reveal characteristic findings in MFS patients.

COVID-19 Emergence and Neurological Implications

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVID-19), was first identified in December 2019 in Wuhan, China. The World Health Organization (WHO) declared COVID-19 a pandemic on March 11, 2020.

Since the onset of the pandemic, a myriad of neurological symptoms and complications have been reported alongside the typical respiratory manifestations. While common neurological complaints in COVID-19 patients include anosmia, ageusia, and headache, more severe manifestations such as stroke, impaired consciousness, seizures, and encephalopathy have also been observed.

As of January 2023, a total of 25 cases of COVID-19-associated MFS have been reported, including instances involving children. This has raised questions about the potential link between COVID-19 and MFS. The pathogenesis of MFS, whether triggered by SARS-CoV-2 or other microbial agents, is postulated to involve molecular mimicry or a maladaptive immune response to infection.

By December 23, 2022, over 650 million COVID-19 cases had been diagnosed, leading to over six million deaths worldwide. The emergence of postvaccine MFS cases linked to COVID-19 vaccines, amid the vaccination of approximately 2.5 billion individuals with 13 billion doses, has further spurred interest in understanding the relationship between COVID-19 and MFS.

Clinical Features of COVID-19-Associated MFS

COVID-19-related MFS cases exhibit diverse clinical presentations, with some patients experiencing severe COVID-19 symptoms requiring hospitalization while others have a milder clinical course. Strikingly, some individuals develop MFS symptoms despite never exhibiting symptomatic COVID-19, suggesting that MFS can potentially manifest in anyone exposed to SARS-CoV-2, irrespective of disease severity. This observation underscores the complex interplay between COVID-19 and MFS, necessitating further investigation through epidemiological studies and large cohort analyses.

Pathogenesis of MFS: Molecular Mimicry and Beyond

Antecedent infections, often involving pathogens such as Campylobacter jejuni and Hemophilus influenza, have traditionally been implicated in the pathogenesis of MFS via molecular mimicry. However, MFS can also arise without a clear causative pathogen. Since the emergence of the COVID-19 pandemic, cases of MFS associated with COVID-19 have been reported worldwide. These cases have prompted a closer examination of the immunological mechanisms at play in MFS.

Molecular mimicry between peripheral nerve components and microbial/viral antigens is believed to occur through the activation of the adaptive immune system.

Anti-GQ1b antibodies, which target ganglioside GQ1b, are a hallmark of MFS and can block acetylcholine release from motor nerve terminals, contributing to neuromuscular transmission defects. Notably, anti-GQ1b antibodies are typically found in MFS cases with ophthalmoplegia and GBS but not in GBS cases without ophthalmoplegia. This selective antibody presence highlights the specific involvement of oculomotor nerves and associated ganglioside epitopes in MFS pathogenesis.

However, some atypical clinical presentations in anti-GQ1b antibody-negative cases have been documented. These cases are more prevalent in males and tend to manifest at a younger age. Gastroenteritis is often associated with the onset of symptoms in these cases. While anti-GQ1b antibodies are crucial diagnostic markers in classic MFS, they may not be as reliable in COVID-19-associated MFS. Interestingly, anti-GQ1b antibody positivity is more frequent in MFS cases associated with COVID-19 vaccination, raising questions about alternative mechanisms in play.

Clinical Diagnosis and Investigations

MFS is primarily diagnosed based on its characteristic triad of ataxia, areflexia, and ophthalmoplegia. However, these symptoms may not always manifest simultaneously, with diplopia and ataxia sometimes being the initial presenting complaints. Ophthalmoplegia, often bilateral and symmetric, predominantly involves the oculomotor nerve. Areflexia is a consistent finding in MFS, affecting all deep tendon reflexes, and may develop later in the upper limbs. The absence of deep tendon reflexes is observed in about 81% of MFS cases.

Electroneuromyography (ENMG) studies in MFS patients reveal variable findings, including reduced sensory nerve action potentials (SNAPs) amplitude and absent H reflexes. Sensory involvement is more common in nerve conduction studies (NCSs).

Motor fiber NCSs are generally normal, but some cases show abnormalities such as prolonged distal motor latencies (DML), decreased compound muscle action potential (CMAP) amplitude, and normal/slow motor conduction velocities (MCVs).

F-wave latencies, late responses, and H reflex findings also vary but are collectively indicative of demyelinating conduction block in proximal nerve segments.

While brain MRI is usually normal in MFS cases, some reports mention T2 hyperintense images in cranial nerves and posterior spinal cord columns, particularly in the brain.

Treatment and Prognosis

Unlike GBS, MFS patients typically do not require immunotherapy. The condition often has a good prognosis with spontaneous recovery. Immunomodulatory treatments such as plasma exchange (PE) and intravenous immunoglobulin (IVIg) have shown benefits in GBS and are occasionally used in MFS cases with severe symptoms. However, these treatments are not considered standard in MFS due to the generally favorable outcome without intervention. Symptoms of ophthalmoplegia and ataxia tend to improve within one to three months after onset, but areflexia may persist without functional impairment.

Conclusion and Future Directions

In conclusion, the emergence of COVID-19-associated MFS cases has added a new layer of complexity to our understanding of this rare neurological disorder. While molecular mimicry and anti-GQ1b antibodies play a significant role in MFS pathogenesis, their presence and relevance in COVID-19-related MFS cases remain uncertain. Continued research is essential to elucidate the mechanisms behind this association and explore potential alternative pathways.

Large-scale epidemiological studies and molecular investigations are warranted to unravel the intricacies of the relationship between COVID-19 and MFS. As the COVID-19 pandemic persists with evolving variants, ongoing research will be crucial in uncovering how the virus affects the nervous system and contributes to neurological complications like MFS. Further systematic reviews and molecular studies will shed light on the underlying mechanisms and help guide clinical management and treatment strategies for this rare syndrome in the context of COVID-19.

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